Fetal alcohol syndrome and related disorders occur in approximately 1% of live births in the United States and represent the most common cause of mental retardation. Fetal alcohol syndrome is commonly associated with significant lifetime disability, and thus the prevention and treatment of this syndrome is greatly needed. Normally, microglia protect neurons through the production of neurotrophic factors. However, microglia are resident CNS macrophages which play a critical role in the innate immune response to pathogens. Ethanol causes activation of microglia which may contribute to neuropathogenesis. Toll-like receptors (TLRs) respond to pathogens and endogenous "danger signals" produced following trauma or tissue injury. The mechanisms by which alcohol modulates microglia-neuronal interactions and neuropathogenesis in animal models of fetal alcohol syndrome have not been elucidated. The general hypothesis of the proposed studies is that TLRs expressed on microglia play a critical role in modulating ethanol induced neurodegeneration in the developing nervous system. The Specific Aims of the proposed research are as follows: f Specific Aim 1: Determine the mechanisms by which microglial TLRs modulate response to alcohol and neurodegeneration. The effects of alcohol on TLR signaling pathways in vitro will be examined in primary microglia. The role of specific TLR signaling molecules will be assessed in these studies utilizing microglia derived from animals in which these molecules have been knocked out. Co-culture paradigms will be used to assess the role of TLRs in modulating alcohol effects on neuron viability. f Specific Aim 2: Determine the effects of TLRs in modulating neurodegeneration in vivo in animal models of fetal alcohol syndrome. The effects of ethanol on specific TLR signaling pathways will be evaluated in studies utilizing animals in which key TLR signaling molecules have been knocked out. We have demonstrated that specific nuclear receptor agonists alter TLR signaling in microglia. We will evaluate the therapeutic potential of these agonists in modulating alcohol induced neurodegeneration in our animal model of fetal alcohol syndrome. The proposed studies will determine the mechanisms by which TLRs expressed on microglia modulate alcohol induced neurodegeneration in the developing nervous system. These studies have important implications concerning the treatment of fetal alcohol syndrome. PUBLIC HEALTH RELEVANCE: Fetal alcohol syndrome and related disorders occur in approximately 1% of live births in the United States and represent the most common non-genetic cause of mental retardation. Fetal alcohol syndrome is commonly associated with significant lifetime disability, and thus the prevention and treatment of this syndrome is greatly needed. The proposed studies are designed to evaluate the role of "danger signals" produced following alcohol exposure to the developing brain, with the goal of developing future therapies for fetal alcohol syndrome.